title: Inhibition of soluble epoxide hydrolase confers cardioprotection and prevents cardiac cytochrome P450 induction by benzo(a)pyrene.
abstract: We recently demonstrated that benzo(a)pyrene (BaP) causes cardiac hypertrophy by altering arachidonic acid metabolism through the induction of the expression of CYP ω-hydroxylases and soluble epoxide hydrolase (sEH) enzymes. The inhibition of CYP ω-hydroxylase enzymes partially reversed the BaP-induced cardiac hypertrophy. Therefore, it is important to examine whether the inhibition of sEH also confers cardioprotection. For this purpose, male Sprague-Dawley rats were injected intraperitoneally daily with either the sEH inhibitor 1-(1-methanesulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS; 0.65 mg/kg), BaP (20 mg/kg), or the combination of BaP (20 mg/kg) and TUPS (0.65 mg/kg) for 7 days. Thereafter, the heart, liver, and kidney were harvested, and the heart to body weight ratio was measured. The expression of the hypertrophic markers, sEH, heme oxygenase-1, and CYP450 enzymes was determined. Our results demonstrate that BaP alone significantly induced the expression of sEH and CYP ω-hydroxylases in the heart, liver, and kidney tissues. Treatment with TUPS significantly reversed the BaP-mediated induction of the hypertrophic markers, completely prevented the increase in the heart to body weight ratio, and reduced the BaP-induced CYP1A1, CYP1B1, CYP4F4, and CYP4F5 genes in the heart. The current study demonstrates the cardioprotective effect of sEH inhibitor, TUPS, against BaP-induced cardiac hypertrophy and further confirms the role of sEH and CYP450 enzymes in the development of cardiac hypertrophy.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada. hduffy@bidmc.harvard.edu
authors.forename: Mona E
authors.initials: ME
authors.lastname: Aboutabl
authors.forename: Beshay N M
authors.initials: BN
authors.lastname: Zordoky
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Ayman O S
authors.initials: AO
authors.lastname: El-Kadi
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000502:physiology; D001564:Benzo(a)pyrene / Q000009:adverse effects / Q000494:pharmacology*; D015415:Biomarkers / Q000032:analysis; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000502:physiology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D015386:Hazardous Substances / Q000009:adverse effects / Q000494:pharmacology*; D006321:Heart / Q000502:physiology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics; D007668:Kidney / Q000201:enzymology / Q000502:physiology; D008099:Liver / Q000201:enzymology / Q000502:physiology; D008297:Male; D008861:Microsomes / Q000187:drug effects; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C561619:1-(1-methanesulfonylpiperidin-4-yl)-3-(4-trifluoromethoxyphenyl)urea; D015415:Biomarkers; D002316:Cardiotonic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D015386:Hazardous Substances; D010671:Phenylurea Compounds; D010880:Piperidines; D016718:Arachidonic Acid; D001564:Benzo(a)pyrene; D003577:Cytochrome P-450 Enzyme System; D051547:Heme Oxygenase-1; D004851:Epoxide Hydrolases; C529022:EPHX2 protein, rat